BRUCELLOSIS

1. BRUCELLOSIS Meral SÖNMEZOĞLU, MD Yeditepe University Hospital Professor of Department of Infectious Diseases and Microbiology

2. Learning Objectives • Appreciate the importance for our country and epidemiology • Know clinical features of brucellosis • Understand laboratory diagnosis of brucellosis • Describe the treatment of brucellosis

3. BRUCELLOSIS • Known as “undulant fever”, “Mediterranean fever” or “Maltafever” • Is a zoonosis and the infection is almost invariably transmitted bydirect or indirect contact with infected animals or their products. • It affectspeople of all age groups and of both sexes.

4. There still remainregions where the infection persists in domestic animals and, consequently,transmission to the human population frequently occurs. • It is an importanthuman disease in many parts of the world especially in the Mediterraneancountries of Europe, north and east Africa, the Middle East, south and centralAsia and Central and South America

5. BRUCELLOSIS • Brucellosis is probably the commonest anthropozoonotic infection worldwide • A zoonotic infection of domesticatedand wild animals, caused by organisms of the genusBrucella. • Humans become infected by ingestionof animal food products, direct contact with infectedanimals, or inhalation of infectious aerosols.

6. Brucella melitensis remains the majorcause of human disease worldwide, • followed by B. abortus and B. suis, • while rare but persisting cases of B.canis human infection

7. BRUCELLOSIS • Humans, who are usually infected incidentallyby contact with infected animals or ingestionof dairy foods, may develop numerous symptomsin addition to the usual ones of fever, malaise, andmuscle pain. • Disease frequently becomes chronicand may relapse, even with treatment

8. In an era of rapid emergence of antimicrobial resistance, controversies regarding the prolonged use of antibiotics with established activity against Brucella pose special problems. • In some endemic regions, especiallyin the developing world, brucellosisand tuberculosis coexist in the same communities.

9. Microbiology • Brucellae are small, nonmotile, nonsporulating, nontoxigenic, nonfermenting, aerobic, Gram-negative coccobacilli that may, based on DNA homology,represent a single species. • Conventionally,however, they are classified into six species, each comprising several biovars

11. The 7 Currently Recognized Brucella Species

12. Microbiology • Brucellae grow best on trypticase, soy-based, orother enriched media with a typical doubling timeof 2 hours. • Most biovars of B abortus require incubationin an atmosphere of 5% to 10% carbon dioxidefor growth. • Brucellae may produce urease, oxidizenitrite to nitrate, and are oxidase and catalasepositive. • Species and biovars are differentiated by their carbon dioxide requirements

13. Microbiology • The lipopolysaccharide (LPS) component of theouter cell membranes of brucellae is quite different—both structurally and functionally—from that of other Gram-negative organisms • The complete sequencing of the B. melitensis was achieved in 2002. • B. suis and abortus recently.

14. Pathogenesis • Brucella species have a unique ability of invading both phagocytic and nonphagocytic cells and surviving in the intracellular environment by avoiding the immune system in different ways, • explaining why brucellosis is a systemic disease and can involve almost every organ system

15. Pathogenesis • Although humoral antibodies appear to play some role in resistance to infection,the principal mechanism of recovery from brucellosis is cell-mediated. • Cellularimmunity involves the development of specific cytotoxic T lymphocytes andactivation of macrophages, enhancing their bactericidal activity, through therelease of cytokines

16. Pathogenesis

17. Pathogenesis Cultured human monocyte-derived macrophage infected with Brucella melitensis. The bacteria, which replicate in phagolysosomes, have a coccobacillary appearance

18. Pathogenesis • Brucella species have relatively low virulence, toxicity, and pyrogenicity, making them a poor inducer of some inflammatory cytokines such as tumor necrosis factor (TNF) and interferons • After replication in the endoplasmic reticulum, the brucellae are released with the help of hemolysins and induced cell necrosis

19. Epidemiology • Brucellosis causes more than 500,000 infections per year worldwide. • The heaviest disease burden lies in countries of the Mediterranean basin and Arabian Peninsula, • Also common in India, Mexico, and South and Central America • Because of variable reporting, true estimates in endemic areas are unknown. Incidence rates of 1.2-70 cases per 100,000 people are reported.

20. The Global Incidence of Human Brucellosis

23. Morbidity and Mortality • Human brucellosis carries a low mortality rate (< 5%), mostly secondary to endocarditis, which is a rare complication of brucellosis. • However, brucellosis can cause chronic debilitating illness with extensive morbidity. • Worldwide, brucellosis is more common in males than in females, with a ratio of 5:2-3 in endemic areas • Persons in their third to fifth decades of life were most commonly affected.

24. Clinical Presentation • Fever is the most common symptom and sign of brucellosis, occurring in 80-100% of cases. It is intermittent in 60% of patients with acute and chronic brucellosis and undulant in 60% of patients with subacute brucellosis. Fever can be associated with a relative bradycardia

26. Clinical Presentation • Constitutional symptoms of brucellosis include anorexia, asthenia, fatigue, weakness, and malaise and are very common (>90% of cases). • Bone and joint symptoms include arthralgias, low back pain, spine and joint pain, and, rarely, joint swelling. These symptoms affect as many as 55-80% of patients

27. Physical The most common findings include hepatosplenomegaly (or isolated hepatomegaly or splenomegaly) and osteoarticular involvement.

28. Physical • Osteoarticular findings can include tenderness and swelling over affected joints, bursitis, decreased range of motion, and joint effusion (rare). • Maneuvers that isolate the sacroiliac joint may cause pain

29. Symptoms and Signs of Brucellosis

31. Complications • Osteoarticularcomplications • Bone and joint involvement are the most frequent complications of brucellosis,occurring in up to 40% of cases • Gastrointestinalcomplications • Foodborne brucellosis resembles typhoid fever, in that systemicsymptomspredominateovergastrointestinalcomplaints • Hepatobiliarycomplications • The liver is commonly involved in brucellosis, although liver function tests canbe normal or only mildly elevated • Genitourinarycomplications • Orchitis and epididymitis are the most frequentgenitourinary complications of brucellosis in men

32. Complications • Cardiovascularcomplications • Infective endocarditis is the most common cardiovascular manifestation, andit is said to be the most common cause of death from brucellosis • Aortic valve is involved more often than the mitral valve • Neurologicalcomplications • Neurobrucellosis refers to a variety of neurological complications associatedwithbrucellosis, meningitisormeningoencephalitisare the most common manifestations. • Cutaneouscomplications • Opthalmiccomplications

33. Complications • Cutaneous manifestations develop in 5-10% of patients, are transient and nonspecific, resolve with therapy, and do not alter the prognosis. Lesions reported in association with brucellosis are as follows:[17] Erythema nodosum, abscesses, and papulonodular eruptions (most common) • Impetigo, psoriatic, eczematous, and pityriasis rosea –like lesions • Macular, maculopapular, and scarlatiniform rashes • Vasculitic lesions (eg, petechiae, purpura, thrombophlebitis) • Ocular findings can include the following:[18] Uveitis[19] • Keratoconjunctivitis • Iridocyclitis • Nummular keratitis • Choroiditis • Optic neuritis[20] • Metastatic endophthalmitis • Cataracts

34. Differential diagnoses • Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy • Cryptococcosis • Hepatitis, Viral • Histoplasmosis • Infectious Mononucleosis • Infective Endocarditis • Influenza • Leptospirosis • Malaria • Tuberculosis • Tuberculosis of the Genitourinary System • Typhoid Fever

35. Diagnosis • Culture • blood cultures with improved techniques such as the Castaneda bottles • Subcultures are still advised for at least 4 weeks • Bone marrow culture is thought to be the criterion standard • Any fluid can be cultured (eg, synovial, pleural, cerebrospinal • CSF evaluation

37. Culture

38. Diagnosis • Serology Serological testing is the most commonly used method of brucellosis diagnosis. • Serum tube agglutination test • Tray agglutination (TAT) and modified TAT are also popular. Titers of more than 1:160 in conjunction with compatible clinical presentation is considered highly suggestive of infection • ELISA: cytoplasmic proteins as antigens and measures IgM, IgG, and IgA, • Polymerase chain reaction (PCR):

40. Imaging • Chest radiography :hilar and paratracheal lymphadenopathy, pulmonary nodules, pleural thickening, and pleural effusion. • Spinal radiography : • sacroiliitis, the most commonly observed abnormalities include blurring of articular margins and widening of the sacroiliac spaces • Spondylitis-related abnormalities include anterosuperior vertebral angle epiphysitis, spinal straightening, narrowing of the intervertebral disc spaces, end-plate sclerosis, and osteophytes • Radionuclide scintigraphy

41. Histology Histologic findings in brucellosis usually include mixed inflammatory infiltrates with lymphocytic predominance and granulomas (in up to 55% of cases) with necrosis Well-formed hepatic granuloma from a patient with brucellosis

42. Treatment • The goal of medical therapy in brucellosis is to control symptoms as quickly as possible to prevent complications and relapses. • Multidrug antimicrobial regimens are the mainstay of therapy because of high relapse rates reported with monotherapeutic approaches. • The risk of relapse is not well understood, as resistance is not a significant issue in treating brucellosis

43. Treatment • A meta-analysis performed in 1995 evaluated the efficacy of the two WHO-recommended regimens and concluded that the efficacy of the doxycycline-streptomycin (DOX-STR) regimen was superior to that of the doxycycline-rifampicin (DOX-RIF) regimen, as already suggested by previous studies

45. Treatment • InNovember 2006, a consensusmeeting aimed at reaching a commonspecialist statement on the treatmentof brucellosis was held in Ioannina,Greece under the auspices of theInternationalSociety of Chemotherapyand the Institute of Continuing MedicalEducation of Ioannina

47. Recommendations of Ioannina Concensus

48. Treatment

49. Treatment • The essential element in the treatment of all forms of human brucellosisis the administration of effective antibiotics for an adequate length of time. • Treatment of uncomplicated cases in adults and children eight yearsof age and older: • Doxycycline 100 mg twice a day for six weeks +streptomycin 1 g daily for two to three weeks. • OR • Doxycycline 100 mg twice a day for six weeks + rifampicin 600–900 mg daily for six weeks.

50. Treatment